Adaptive immune memory that protects against microbial infection is traditionally thought to be mediated by T cells circulating in blood and through secondary lymphoid tissues. According to this view, while memory T cells can be readily mobilized from blood to peripheral epithelial tissues to fight infection, they would return to blood and lymph nodes once the infection was resolved. This transformative R01 application challenges this prevailing paradigm. Very recently, we and others have demonstrated memory T cells can be found in abundance in the peripheral tissues of both humans and mice, with the majority of this work being done in skin. Under normal conditions, twice as many T cells reside in normal human skin as in blood. Skin- homing memory T cells are 20-fold more abundant in normal skin than in blood. These skin resident memoryT cells (TRM) have a diverse T cell receptor repertoire, can be readily activated through the TCR or by cytokines, are polyfunctional, and have great proliferative potential. Therefore, TRM are not simply memory T cells in an unexpected location. Rather, they are a unique and incompletely characterized population, having many functional and phenotypic qualities that differentiate them from memory T cells that circulate in blood. Evidence is accumulating that similar populations of TRM exist in lung and GI tract, as well as reproductive mucosa. There is a growing body of evidence in murine models suggesting that T cells are recruited to skin and other epithelial tissues after pathogen challenge, and then can persist there long term as TRM. At least two separate studies examining viral infection of skin have demonstrated that these TRM, rather than antibody or TCM recruited from blood, provide principal protection against viral challenge, even many months after resolution of the initial infection. Similar populations of T cells are being identified after infection in lung, GI tract, and even CNS. These TRM consist largely of T cells that were originally (as naove T cells) activated in lymph nodes draining that tissue, and thus represent a resident armada of tissue specific T cells specific for tissue selective pathogens. We thus propose a paradigm-shifting hypothesis: that protective immune memory is mediated largely by TRM that have accumulated over time in epithelial tissues. We propose that vaccination strategies against pathogens should be designed specifically to enhance the generation of these peripheral epithelial TRM PUBLIC HEALTH RELEVANCE: Adaptive immune memory that protects against microbial infection is traditionally thought to be mediated by T cells circulating in blood and through secondary lymphoid tissues. We thus propose a paradigm-shifting hypothesis: that protective immune memory in humans is mediated principally by previously unappreciated and uncharacterized populations of unique memory T cells resident to epithelial tissues (TRM) that have accumulated over the life of the host. Vaccination strategies against pathogens should thus be designed specifically to enhance the generation of these protective TRM.